Asthma is a chronic respiratory disease with a global human and economic burden on patients, and society. Asthma treatment mainly consists of inhaled corticosteroids and bronchodilators, which enable adult populations to function well despite the disease. Small airway inflammation is particularly important in the pathogenesis of asthma in children, and hence the ability to target this area of the lung efficiently with inhaled corticosteroids is of major importance. Current options for delivering corticosteroids to small children include cumbersome nebulizer formulations and oral syrups, but the inefficiency of these methods to target the small airways result in an unnecessary amount of systemic exposure to corticosteroids. Savara has developed a novel technology to reformulate the most commonly used inhaled corticosteroid in small children, budesonide, into a NanoCluster dry powder composed of particles ranging 1-2 5m in median aerodynamic size, which is ideal for effective delivery to the distal airways. In addition, the formulations have improved solubility, and are composed of almost pure budesonide due to the elimination of carrier substances. Savara's powder technology will be combined with a novel inhaler device that electronically triggers the aerosolization when the patient reaches an inhalation flow rate sufficient to deliver the drug to the deep lung. The combination of Savara's high performance inhalation powder with this "Pediatric Inhaler" that is not sensitive to the special inhalation profiles of small children, i.e. small volume of inhalation with variable force and duration, will be a major advance in pediatric asthma therapy. The first aim of this proposal is to optimize Savara's preliminary budesonide NanoCluster formulations using two different processes, solvent diffusion and bead milling. Systematic experiments will be conducted to investigate the effect of the drug concentration in solution, the feed rate of solution into non-solvent, the degree of mixing, and the use, nature and concentration of excipients. Alternatively, for the bead-milling process, key variables, such as milling media diameter, drug concentration in suspension, shear force during milling, duration of milling, and the use, nature, and concentration of excipients, will be evaluated. In Aim 2, budesonide NanoCluster powder, produced by the process selected as a result of Aim 1 will be filled into aluminum foil blisters and the aerosol performance of the NanoCluster formulation delivered by the Pediatric Inhaler will be evaluated through cascade impactor studies using conditions that simulate inhalation patterns in small children. In Aim 3, successful formulations will be produced in three small batches that will be subjected to stability studies. IND-enabling aerosol performance of the budesonide NanoCluster Pediatric Inhaler system, including batch-to-batch reproducibility of the powders and fillings, as well as the results of the stability studies will be documented in preparation for clinical trials. PUBLIC HEALTH RELEVANCE: Small airway inflammation is particularly important in the pathogenesis of asthma in children, and hence the ability to efficiently target this area of the lung efficiently is of high importance. Current options for delivering corticosteroids to small children (<6 years of age) include cumbersome nebulizer formulations and oral syrups, but the inefficiency of these methods to target the small airways result in an unnecessary amount of systemic exposure to corticosteroids. Savara proposes to apply its NanoCluster technology to reformulate budesonide into a highly efficient inhalation powder that in conjunction with a special pediatric inhaler allows effective treatment of the asthmatic airway inflammation in small children with reduced systemic steroid exposure and substantially reduced administration times.